Simultaneously stimulating both brain hemispheres by rTMS in patients with unilateral brain lesions decreases interhemispheric asymmetry

Abstract

Background:

Interhemispheric asymmetry caused by brain lesions is an adverse factor in the recovery of patients with neurological deficits. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate cortical oscillation and proposed as an approach to rebalance the symmetry, which has not been documented well.

Objective:

In this study, we investigated the influence of repetitive transcranial magnetic stimulation (rTMS) on EEG power in patients with unilateral brain lesions by simultaneously stimulating both brain hemispheres and to elucidate asymmetrical changes in rTMS-induced neurophysiological activity.

Methods:

Fourteen patients with unilateral brain lesions were treated with one active and one sham session of 10 Hz rTMS over the vertex (Cz position). Resting-state EEGs were recorded before and immediately after rTMS. The brain symmetry index (BSI), calculated from a fast Fourier transform, was employed to quantify the power asymmetry in both hemispheres and paired channels over the entire range and five frequency bands (delta, theta, alpha, beta and gamma bands).

Results:

Comparison between active and sham sessions demonstrated rTMS-induced EEG after-effects. rTMS in the active session significantly reduced the BSI in patients with unilateral brain lesions over the entire frequency range (t = 2.767, P = 0.016). Among the five frequency bands, rTMS only induced a noticeable decrease in the BSI in the delta band (t = 2.254, P = 0.042). Furthermore, analysis of different brain regions showed that significant changes in the BSI of the alpha band were only demonstrated in the posterior parietal lobe. In addition, EEG topographic mapping showed a decreased power of delta oscillations in the ipsilesional hemisphere, whereas distinct cortical oscillations were observed in the alpha band around the parietal-occipital lobe in the contralesional hemisphere.

Conclusions:

When both brain hemispheres were simultaneously activated, rTMS decreased interhemispheric asymmetry primarily via reducing the delta band in the lesioned hemisphere.

Keywords

Brain symmetry index oscillation repetitive transcranial magnetic stimulation resting-state EEG unilateral brain lesions

1 Introduction

A striking feature in brain-lesioned patients is a disrupted interhemispheric excitability balance that is in part responsible for abnormal cortical activity and neurological disorders (Farias da Guarda et al., 2010). Ischemic stroke generates abnormal, slow-wave activity, particularly in the delta band, and attenuates normative, faster activity, particularly in the alpha and beta band (Bentes et al., 2018). In addition, it has been showed that an increase in slow-wave activities in the unilateral lesioned-area negatively correlated with cognition (Schleiger et al., 2014). Significant evidence has indicated that motor impairment correlated with asymmetry in the alpha and beta bands in which loss of power in the alpha band and increased power in the beta band in the ipsilesional central cortical area signified a poor motor outcome (Stinear, 2017; Thibaut et al., 2017). Similarly, the interhemispheric competition hypothesis suggested that balancing excitability between ipsilesional and contralesional hemispheres was an indicator of improved behavior in stroke patients (Corti et al., 2012). In a previous study, a treatment strategy was presented to highlight the importance of interhemispheric balancing that showed that inhibition of cortical activity in the unaffected hemisphere has a therapeutic effect on stroke recovery (Sebastianelli et al., 2017). Therefore, modulating abnormal cortical activity and rebalancing interhemispheric activities is a meaningful approach to achieve neurological improvements in patients with brain lesions.

Rehabilitative interventions have shown to improve functional outcomes by promoting adaptive functional and structural plasticity in the brain, which can be induced by non-invasive brain stimulation (NIBS) treatments (Lefaucheur et al., 2020). Transcranial magnetic stimulation (TMS) is a type of NIBS technique that modulates cortical excitability and has shown significant therapeutic promise in the treatment of neurological disorders (Cirillo et al., 2017). Repetitive TMS (rTMS) is a type of TMS that is characterized by the output of many pulses, which can temporally influence cortical activity beyond the stimulation period and spatially beyond the stimulation site (Siebner & Rothwell, 2003). Protocols involving low-frequency (≤1 Hz) and high-frequency (≥5 Hz) rTMS have strong dichotomy; the former decreases cortical excitability whereas the latter in general produces facilitating oscillatory activity (Reid, 2003). In general, cortical oscillatory activities are assumed to play an important role in behavior, and oscillatory abnormalities may be one of the pathophysiological manifestations of neurological disorders (Assenza et al., 2017). For example, high alpha oscillatory power positively relates to corticospinal excitability (Thies et al., 2018), and poor motor performance can result from decreased synchrony of alpha oscillations between affected brain regions and the remainder of the brain (Dubovik et al., 2013). However, it remains unclear whether rTMS can reduce the interhemispherical asymmetry in oscillatory brain activities. Electroencephalograph (EEG) recordings have shown that the effects of rTMS on behavior are the consequence of oscillatory dynamics rather than creating a “virtual lesion” (Johnson et al., 2010). These findings indicate that EEG reactivity may be a promising method to help understand how rTMS affects brain activities.

Ipsilesional and contralesional hemispheres play different roles in stroke recovery as increased excitability in the contralesional hemisphere can hamper the recovery by inhibiting the ipsilesional hemisphere (Dodd et al., 2017). In a number of studies, cortical activities were investigated by stimulating the unilateral hemisphere with different rTMS protocols (Lee et al., 2019; McAllister et al., 2013; Park et al., 2014). Ipsilesional activation, which is indicative of reduced bilateral activation, has significantly predicted larger treatment-induced behavioral gains for stroke patients (Burke Quinlan et al., 2015). rTMS with a high frequency over the lesioned hemisphere and with a low frequency over the non-lesioned hemisphere are common methods in modulating the cortical excitability, however, there are currently no available studies to explore which is responsible for rebalancing the interhemispheric symmetry in rhythmic neuronal activities in patients with unilateral brain lesions.

Therefore, in this study, we investigated EEG after-effects in patients with unilateral brain lesions after simultaneous stimulation of both hemispheres by rTMS to determine whether rTMS could reduce interhemispheric asymmetry and to define the contribution of the lesioned hemisphere or the non-lesioned hemisphere in the reduction of interhemispheric asymmetry.

2 Methods

2.1 Patients

In this study, a total of 14 patients were enrolled according to the inclusion and exclusion criteria. The inclusion criteria were as follows: (1) age ranged between 18 years and 70 years; (2) unilateral lesions proven by CT or MRI; (3) first-ever brain injury; (4) one-to-six months post-brain injury; and (5) no other neurological/psychiatric conditions. The exclusion criteria were as follows: (1) a history of epilepsy within one month; (2) a pacemaker or other metallic implants in head; (3) a skull defect; or (4) serious complications, including heart failure or renal failure. This study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of Nanfang Hospital, Southern Medical University. All patients and their families were informed about the procedure of this study and gave written informed consent. The demographic and clinical features of all patients are summarized in Table 1.

Table 1
Demographic and clinical features

Patients Age Gender Diagnosis Affected side Location Month since injury

P1 28 Male Hemorrhagic L Subcortical 1.5

P2 27 Male Hemorrhagic L Cortical 1

P3 70 Male Hemorrhagic L Subcortical 3.5

P4 47 Male Hemorrhagic L Subcortical 2

P5 43 Male Hemorrhagic L Subcortical 1

P6 51 Male Hemorrhagic L Subcortical 1.5

P7 29 Male Ischemia L Cortical 2

P8 37 Male Ischemia L Cortical 1

P9 52 Male Ischemia L Cortical 1

P10 56 Male Hemorrhagic L Subcortical 6

P11 38 Male Hemorrhagic L Subcortical 1

P12 64 Male Ischemia L Cortical 1

P13 46 Male Hemorrhagic L Subcortical 1

P14 55 Female Hemorrhagic L Subcortical 1

Patients	Age	Gender	Diagnosis	Affected side	Location	Month since injury
P1	28	Male	Hemorrhagic	L	Subcortical	1.5
P2	27	Male	Hemorrhagic	L	Cortical	1
P3	70	Male	Hemorrhagic	L	Subcortical	3.5
P4	47	Male	Hemorrhagic	L	Subcortical	2
P5	43	Male	Hemorrhagic	L	Subcortical	1
P6	51	Male	Hemorrhagic	L	Subcortical	1.5
P7	29	Male	Ischemia	L	Cortical	2
P8	37	Male	Ischemia	L	Cortical	1
P9	52	Male	Ischemia	L	Cortical	1
P10	56	Male	Hemorrhagic	L	Subcortical	6
P11	38	Male	Hemorrhagic	L	Subcortical	1
P12	64	Male	Ischemia	L	Cortical	1
P13	46	Male	Hemorrhagic	L	Subcortical	1
P14	55	Female	Hemorrhagic	L	Subcortical	1

L: Left, P1-14: Patient 1–14.

2.2 Stimulation procedures

Prior to active and sham rTMS sessions, the resting motor threshold (RMT) was measured. Electromyography signals were recorded via disposable surface electrodes that were placed at the muscle of the right abductor pollicis brevis. According to the recommendations of the International Federation of Clinical Neurophysiology Committee (Rossini et al., 2015), the stimulation intensity was determined based on the RMT which was defined as the minimum output intensity that evoked a muscle contractions in which at least 5 out of 10 of the contractions had an amplitude of more than 50μV peak-to-peak in the relaxed abductor pollicis brevis. During testing, patients wore the EEG cap to ensure an exact stimulation intensity.

After the RMT was obtained, all patients received one active or sham session of 10 Hz rTMS at the Cz area (Cz position according to the International 10–20 EEG System). TMS pulses were delivered using a stimulator (YRD, Wuhan, China) with a figure-of-eight coil (diameter is 80mm). It was previously shown that both brain hemispheres can be simultaneously activated by one session of rTMS on Cz (de Araújo et al., 2017; Kumru et al., 2016). One session of the rTMS procedure consisted of 1500 pulses (10 Hz, trains of 20 pulses over 2 s and at 30 s intervals) at an intensity of 100%of the RMT.

All patients who participated in this study were required to attend three visits with at least 72 hours between visits. The first visit was designed to obtain the RMT and to set the individual’s rTMS protocol. During the second and the last visit, the active session of rTMS as well as a sham-stimulation were randomly performed. Pre-stimulation and post-stimulation EEG signals were recorded in the active session. The sham-stimulation was carried out with the coil held at 90° to confirm the effects of active rTMS. Pre-stimulation and post-stimulation EEG signals were record.

2.3 EEG data recording and preprocessing

Resting-state EEGs were recorded to obtain at least 10 min of a stable signal before and immediately after rTMS interventions in both active and sham conditions. EEG data were acquired through the EEG System with a TMS-compatible amplifier (NuerOne, Bittium Bio-Signals Ltd, Finland) and an EEG Ag/AgCl cap with nineteen channels (GREENTEK, Wuhan, China). According to the International 10-20 EEG System, the nineteen electrodes were consisted of Fp1, Fp2, F7, F8, F3, F4, C3, C4, P3, P4, T3, T4, T5, T6, O1, O2, Fz, Cz and Pz. The FCz electrode was set as an online reference. The impedance of all electrodes was maintained below 5 kΩ and the sampling rate was 1000 Hz. Patients lay in bed with their eyes closed while awake in a quiet room, and wore earplugs to reduce rTMS-induced noise disturbance. During the rTMS session, the EEG cap was maintained on the patient’s head and to immediately record the signals after termination of the session.

The investigator who performs the data processing was blinded to sham or active session. EEG data were processed offline using EEGLAB14.0 running in MATLAB2018. Data were referenced to an averaged reference and band-pass filtered between 0.5 and 48 Hz. Drifting and non-obvious EEG signals were rejected based on a visual inspection, then, independent component analysis was employed to remove artifact components, including eye blinks and muscle contractions. Cleaned EEG data were extracted for further analysis.

2.4 EEG data processing

Fast Fourier transform (2 s Hamming) was applied to estimate the EEG power at different frequency bands. The absolute power was obtained for the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), gamma (30–40 Hz) and whole (0.5–40 Hz) frequency bands of both hemispheres and all channels (Okamura et al., 2001). The brain symmetry index (BSI) was used to reflect the asymmetry of the two brain hemispheres and paired channels. The BSI equation for hemispheres was as follow: [BSI = Power (L_Hemi-R_Hemi)/Power (L_Hemi +R_Hemi)]. The BSI equation for paired channels was [BSI = Power (C3-C4)/Power (C3 + C4)]. BSI = 0 represents perfect symmetry and that a decrease in BSI corresponds to an increase in symmetry.

2.5 Statistical analyses

The paired t-test was employed to analyze the difference in the BSI between pre-rTMS and post-rTMS under normal distribution at different frequency bands. An mixed ANOVA model was applied to the comparisons among different sessions. Furthermore, post-hoc Bonferroni’s correction was used for multiple comparisons between sessions. The sphericity assumption was assessed using a Mauchly’s test. Greenhouse-Geisser epsilon adjustments for non-sphericity were made where appropriate. Topographical mapping was plotted to show the cortical oscillatory power at different frequency bands. Data analyses and graphic designs were created in SPSS version 20, OriginPro 9, and MATLAB 2018.

Fig. 1

Comparison between sham sessions. The BSI was defined as the absolute power difference between the left and right hemisphere. No significant differences in BSI were found among pre-rTMS and post-rTMS in sham-stimulation sessions in the active sessions.

3 Results

3.1 Comparison between sham and active sessions

Among fourteen patients, there were four patients with ischemia and ten patients with cerebral hemorrhage. Mean duration of illness was 1.8 month (1–6 months). Nine patients were diagnosed as subcortical stroke, and five patients was cortical stroke. To determine if patients with unilateral brain lesions had interhemispheric asymmetry in different frequency bands, the BSI prior to sham rTMS sessions was analyzed in different frequency bands. Significant interhemispheric asymmetry was observed in all frequency bands. Further comparison before and after sham-stimulation was performed to determine whether confounding factors (e.g., noise and time) affected the BSI. No differences were observed in the BSI between hemispheres or between paired channels in all frequency bands after sham-stimulation.

3.2 Effects of rTMS on interhemispheric asymmetry

To elucidate the effects of rTMS on interhemispheric asymmetry, a mixed ANOVA model was employed to evaluate the main and interaction effects of different sessions and timing on BSI. The results showed that the BSI was significantly decreased after one active session of rTMS (main effect: F = 8.844, P = 0.006, df = 1, interaction effect: F = 0.324, P = 0.574, df = 1). As shown in Fig. 2, more in-depth analyses of the different frequency bands revealed that the BSI of the delta band was a significantly reduced (main effect: F = 5.372, P = 0.037, df = 1, interaction effect: F = 0.954, P = 0.347, df = 1) upon induction by rTMS; however, there were no other significant after-effects on BSI induced by rTMS in the other four frequency bands.

Fig. 2

Interhemispheric BSI. The interhemispheric asymmetry of the whole frequency range in post-rTMS was significantly less than in pre-rTMS after active session. At different frequency bands, the BSI was significantly decreased only in the delta band after active session. No significant difference was found in sham session. An asterisk refers to a significant difference in the rTMS pre-post comparison with a P-value below 0.05.

3.3 Effects of rTMS on asymmetry in paired channels

In this study, eight paired-channels were compared at different frequency bands and showed that rTMS significantly induced EEG after-effects in channels P3 and P4 and O1 and O2. Moreover, the BSI was significantly increased in the alpha band (Fig. 3) in those four channels. However, no significant BSI after-effects were observed in any of the other frequency bands in all channels (for details, see supplementary files).

Fig. 3

BSI in paired channels. Only P3 and P4 and O1 and O2 are shown. A significant difference in alpha bands was found in channels P3 and P4 and O1 and O2. The BSI in pre-rTMS was significantly lower than in post-rTMS. An asterisk denotes a significant difference with a P-value below 0.05. Other channels can be found in the supplementary files (https://figshare.com/articles/BSI_in_paired_channels_xlsx/11956332).

3.4 Cortical oscillatory power at different frequency bands

Figure 4 shows the distribution of the cortical oscillatory power at different frequency bands before and immediately after rTMS. In most of the patients, the delta wave was primarily localized in the lesioned area and rTMS reduced its oscillatory power. In addition, rTMS induced visible alpha oscillations around the posterior parietal area (P3 and P4), particularly in the contralesional hemisphere.

Fig. 4

Topographical distribution of pre-post rTMS. The left hemisphere is the lesioned side. The left column is pre-rTMS (A and B) and the right column is post-rTMS (C and D). The topographical distribution of delta power focused on the left side and showed a visible reduction after rTMS (A and C). Oscillations in the alpha band were more prominent and mainly distributed in the parietal-occipital area (B and D).

4 Discussion

In the present study, one session using a 10 Hz rTMS protocol was performed on patients with unilateral brain lesions to investigate how rTMS over the vertex affects the interhemispheric asymmetry in these patients by measuring neurophysiological activity. Our data showed that rTMS ameliorated the interhemispheric asymmetry in patients with unilateral brain lesions and this amelioration may be related to a reduction in delta waves in the ipsilesional hemisphere, even though the lesioned and non-lesioned hemispheres were simultaneously activated. Moreover, the rTMS protocol used in this study induced cortical oscillations around the alpha-predominant area (posterior parietal lobe), particularly in the contralesional hemisphere.

Rhythmic oscillations, mainly consisting of the delta, theta, alpha, beta, and gamma frequency bands, are generated from groups of neurons and play a crucial role in functional cortical activities (Rabiller et al., 2015).. Brain oscillations reflect rhythmic fluctuations of local field potentials between excitatory and inhibitory states of neural populations, and greatly help our understanding of brain function (Hanslmayr et al., 2011). During wakefulness, delta activity was almost absent in physiological conditions, but appeared in patients with brain injury. Because alpha-band activity is the dominant oscillation in the awake human brain, high alpha power may indicate internally oriented brain states, whereas low alpha power may indicate externally oriented brain states (Jensen & Mazaheri, 2010). In the healthy brain, the distribution and power of different frequency bands in the left and right hemispheres are identical, and is known as interhemispheric balance (Malyutina et al., 2018).

In the brains of patients with unilateral brain lesions, there is decreased cortical excitability in the lesioned hemisphere and increased excitability in the contralesional hemisphere (Di Pino et al., 2014). Previous studies have shown that this imbalance is an impedance to stroke recovery, which is further supported by outcome improvement as a result of inhibition of the hyper-excitability of the contralesional side by brain stimulation techniques, such as transcranial direct current stimulation (tDCS) and rTMS (Blesneag et al., 2015; Hertenstein et al., 2019). In line with the data presented in previous studies, our findings also demonstrated an apparent asymmetry between the ipsilesional and contralesional hemispheres in the brains of patients with unilateral brain lesions. Brain lesions caused by stroke or TBI can disrupt the interhemispheric balance and subsequently cause some adverse outcomes. Furthermore, stroke patients have significantly more interhemispheric asymmetries when compared to healthy controls. For example, the BSI at early stages after stroke correlates with the Fugl-Meyer motor scores in the recovery stage (Agius Anastasi et al., 2017). Thus, rebalancing the interhemispheric symmetry is a therapeutic strategy in improving the stroke outcome.

In this study, we demonstrated that one session of rTMS can ameliorate brain asymmetry in patients with unilateral brain lesions and has great potential on the restoring the interhemispheric balance in these patients. These conclusions are in line with data that showed that rTMS can reduce neurophysiological imbalance during depression and result in improvements in neuropsychological test scores (Spampinato et al., 2013). The asymmetry or imbalance as a result of unilateral brain injury is not only the result of local lesions, but also because of the interaction of the contralesional side via the corpus callosum (Murase et al., 2004; Takeuchi et al., 2012). In addition, many dysfunctions that occur after brain injury, such as motor function (Murase et al., 2004), unilateral neglect (Fu et al., 2017), and aphasia (Rutar Gorišek et al., 2016), have been reported to be related to the interhemispheric imbalance.

An increase in slow-wave bands (delta and theta) in the lesioned hemisphere has been acknowledged as a remarkable sign in patients with brain lesions and is considered a potential cause to of interhemispheric asymmetry (Fanciullacci et al., 2017; Lu et al., 2001). Furthermore, our results showed that activities of the delta band are mainly localized in the lesioned hemisphere. Higher delta activity indicates a worse outcome after brain injury and is typical of disorders of consciousness (Butz et al., 2004; Leon-Carrion et al., 2008). Importantly, our study showed that interhemispheric asymmetry in the delta band was significantly reduced by one session of 10 Hz-rTMS. Since the effects of rTMS were observed not only in areas local to the stimulation site, but also in remote, anatomically- and/ or functionally- connected sites (Di Lazzaro et al., 2011), we hypothesized that the reduction of delta activity in the perilesional area was related to the activation of neuronal oscillations and the improvement of rTMS-induced neural connectivity. The results were supported by the Kamp et al. study (Kamp et al., 2016) in which they showed that high-frequency rTMS can reduce delta-band activity in patients with schizophrenia. Therefore, we inferred that the significant power reduction in the delta band in the ipsilesional hemisphere may be primarily responsible for decreased rTMS-induced interhemispheric asymmetry in brain-lesioned patients. Furthermore, high-frequency rTMS has been shown to induce high-frequency oscillations, which can reduce the activity of slow-wave bands(Pisani et al., 2015).

The rTMS-induced EEG after-effects were analyzed in different brain regions and we found that the alpha asymmetry in channels P3 and P4 and O1 and O2 was significantly changed after rTMS intervention. In addition, the topographic distribution demonstrated that the alpha oscillatory power in the parietal-occipital area visibly changed after rTMS intervention. Thus, these results indicated that 10 Hz-rTMS effectively facilitate the cortical activities around the alpha-predominant area in the contralesional side. The neurological effects of rTMS depend on the relationship between the frequency of stimulation and endogenous oscillatory activity (Hamidi, 2009; Klimesch et al., 2003). Given that our study did not have experimental rTMS protocols at a different frequency, thus, whether activating the alpha predominant area is associated with the frequency of 10 Hz, is unknown. Increasing evidence suggests that the effects of rTMS on cortical activity are due to the entrainment of frequency oscillations close to the frequency of stimulation (Romei et al., 2016; Thut et al., 2011). In a recent publication, it was shown that the higher the individual alpha frequency (IAF) and the lower the absolute distance of the IAF from the rTMS frequency resulted in greater improvements of symptoms of depression following a six-week course of rTMS (Corlier et al., 2019). We believe that the frequency of rTMS in this study that is close to the endogenous cortical rhythm is crucial for the entrainment of oscillation only in the parietal-occipital area, which implies that endogenous oscillation rhythm in a functional brain network may possibly be a reference in choosing the frequency for rTMS protocols.

The main innovation of this study was to choose the vertex as the stimulation site. Previously, it has been demonstrated that rTMS over the vertex can activate both brain hemispheres simultaneously (de Araújo et al., 2017; Kumru et al., 2016), which were further confirmed by our study. The EEG after-effects under the simultaneous activation present a reduction of delta power in the lesioned hemisphere and increase of alpha power in non-lesioned hemisphere. It is known that a higher power of slow wave in the lesioned hemisphere was the main contribution to the cortical asymmetry (Finnigan et al., 2007). Therefore, reduced rTMS-induced delta power with high frequency over the vertex should be the underlying mechanism to rebalance interhemispheric excitability. Remote network connectivity plays an essential role in facilitating neurological deficits via neuromodulation techniques, which is the underlying mechanism of rTMS over the vertex to reduce the asymmetry (Boddington & Reynolds, 2017). Although rTMS over the lesioned target is the common site in enhancing stroke rehabilitation, our study provides novel insight in rTMS over the vertex when we aimed to reduce the interhemispheric asymmetry.

Certain limitations of our study should be addressed when interpreting the results. One limitation of the study is the relatively small sample size. The use of repeated-measures analysis within-subjects allowed for the satisfactory control of the confound variables. Future studies recruiting more subjects are warranted for confirming the results. In addition, no functional tests were used to verify a therapeutic effect that resulted from rTMS-induced asymmetry reduction. However, we are currently evaluating the therapeutic effects of rTMS on motor function. Finally, the different etiologies of brain injury in the patients in our study potentially decreased the consistency of data, resulting in broad standard deviations.

In conclusion, in this study, we demonstrate that 10 Hz rTMS can decrease the interhemispheric asymmetry in patients with unilateral brain lesions and induce alpha cortical oscillations in the parietal-occipital lobe. The alpha cortical oscillations are more likely in the contralesional hemisphere. The reduction of the delta band from the lesioned hemisphere may be the main contributor to rTMS-induced the benefits. Taken together, rTMS over the vertex can be an underlying treatment to improve the neurological outcomes after stroke via rebalancing the interhemispheric asymmetry.

Competing interests

The authors declare that they have no competing financial interest.

Availability of data

The full datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Footnotes

Acknowledgments

HRH collected the data and drafted the manuscript. YHZ and HJW were involved in the recruitment of the patients. JZF developed guided this study and revised the manuscript. All authors have read and approved the manuscript. This study was supported by the Technology Foundation of Guangdong Province (grant number: 2017B020247001) and the President Foundation of Nanfang Hospital (grant number: 2020CR007). The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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